The emegence of mluti-drug resistant bacteria has led to an increased demand for new antibiotics with new modes of action. The biosynthetic pathway of the bacterial cell wall contains several attractive targets. Some of the enzymes in that pathway are proven targets for antibiotics such as β-lactams and glycopeptides antibiotics.
The bacterial cell wall is a polymer—a single molecule composed of peptidoglycan—that defines the boundary and shape of the cell. Assembled by crosslinking glycan chains with short peptide bridges (Rogers, H. J., H. R. Perkins, and J. B. Ward, 1980, Biosynthesis of peptidoglycan. p. 239–297. In Microbial cell walls and membranes. Chapman & Hall Ltd. London), the completed structure is strong enough to maintain cell integrity against an osmotic pressure differential of over four atmospheres, but also flexible enough to allow the cell to move, grow and divide.
The construction of the peptidoglycan begins in the cytoplasm with an activated sugar molecule, UDP-N-acetylglucosamine. After two reactions (catalyzed by MurA and MurB) that result in the placement of a lactyl group on the 3-OH of the glucosamine moiety, a series of ATP-dependent amino acid ligases (MurC, -D, -E, and -F) catalyze the stepwise synthesis of the pentapeptide sidechain using the newly synthesized lactyl carboxylate as the first acceptor site. After attachment of the sugar pentapeptide to a lipid carrier in the plasma membrane, another glucosamine unit is added to the 4-OH of the muramic acid moiety. The completed monomeric building block is moved across the membrane into the periplasm where the penicillin-binding proteins enzymatically add it into the growing cell wall (Lugtenberg, E. J. J., 1972, Studies on Escherichia coli enzymes involved in the synthesis of Uridine Diphosphate-N-Acetyl-Muramyl-pentapeptide. J. Bacteriol. 110:26–34; Mengin-Lecreulx, D., B. Flouret, and J. van Heijenoort, 1982, Cytoplasmic steps of peptidoglycan synthesis in Escherichia coli. J. Bacteriol. 151: 1109–1117).
Among the potential enzyme targets involved in cell wall biosynthesis is MurC, UDP-N-acetylmuramoyl ligase. This enzyme catalyses the ATP-dependent addition of L-alanine to UDP-N-acetylmuramoyl to form the precursor UDP-N-acetylmuramoyl-L-alanine. This step is essential for cell wall formation in both Gram (−ve) and Gram (+ve) bacteria. Thus, inhibitors of this enzyme are likely broad spectrum antibiotics.